The Nuclear Orphan Receptor Nur77 Is a Lipotoxicity Sensor Regulating Glucose-Induced Insulin Secretion in Pancreatic β-Cells

The NR4A orphan nuclear receptors Nur77, Nurr1, and Nor1 exert multiple cellular and metabolic functions. These transcriptional regulators are activated in response to extracellular stresses, including lipotoxic fatty acids (FA) and proinflammatory cytokines. The contribution of NR4As to beta-cell pathophysiology is, however, unknown. We have therefore examined the role of NR4As as downstream contributors to FA-induced beta-cell dysfunctions. Human pancreatic islets and insulinoma beta-cells were used to determine transcriptional programs elicited by NR4A, which were compared to those triggered by palmitate treatment. Functional studies evaluated the consequence of an increased NR4A expression on insulin biosynthesis and secretion and cell viability in insulinoma beta-cells. FA and cytokine treatment increased NR4A expression in pancreatic beta-cells, with Nur77 being most highly inducible in murine beta-cells. Nur77, Nurr1, or Nor1 modulated common and distinct clusters of genes involved notably in cation homeostasis and insulin gene transcription. By altering zinc homeostasis, insulin gene transcription, and secretion, Nur77 was found to be a major transcriptional mediator of part of FA-induced beta-cell dysfunctions. The repressive role of Nur77 in insulin gene regulation was tracked down to protein-protein interaction with FoxO1, a pivotal integrator of the insulin gene regulatory network. The present study identifies a member of the NR4A nuclear receptor subclass, Nur77/NR4A1, as a modulator of pancreatic beta-cell biology. Together with its previously documented role in liver and muscle, its role in beta-cells establishes Nur77 as an important integrator of glucose metabolism. (Molecular Endocrinology 26: 399-413, 2012)